394
Biotechnology Chap.9
Add - -, Recombinam-c-c ,
nansf~rmed
~:.~l
DNA~'
£.'0"","
l
- Agar :
n ., :::~~
tj ,,,,~,,, _~
DNA
fragments
Transformrecombinant Growcells
joined DNA into
E. coli
cells
rn
0 ~
Agar contains
ampicillin
I<J
Agar contains Two pure cultures containing
tetI1Bcline cloned
lab;;:
DNA
F1gure 9.24 Procedures for obtaining pure clones containing rabbit DNA:
(8) plasmid DNA with resistance to tetracycline and ampicillin is mixed with rabbit
eDNA; (b) DNA ligase is added to join the DNA fragments; (e) E.
coli
cells act as

host; (d) plasmid-containing cells are selected by growth on agar containing
tetracycline, and cells with plasmids joined to rabbit eDNA are identified by
screening on ampicillin-containing agar; (e) and
(f)
these cells grow only on
tetracycline; (g) pure cultures containing cloned genes (from Understanding DNA
and Gene Claning
by
Drlica, Copyright © 1992, Reprinted
by
permission of John
Wiley
&
Sons, Inc.}
Rabbit
DNA
'~::~~~~':l
~(~\\'.'~~p':[f~ ~
IIncubate 37"9
IHeatto60°C)
then cool
@] Mix DNAs Plasmid DNA cut Endonuclease
I>
and enzyme m amp" gene inactivated
( . Replica plate
3
Replica plate
"No colony
I-No colony
9.9 Bioprocess Engineering

39.
The eDNA could then be isolated, made single-stranded (typically by boiling),
and radioactively labeled.
9.8.7 Step 5: Final Screening by Nucleic Acid Hybridization
to Isolate Genomic Clones (Bottom of Figure 9.231
The final step is to screen the colonies grown from the phages containing the orig-
inal fragmented rabbit DNA and to find which ones have the desired hemoglobin
genes (recall this is on the right side of Figure 9.23).The DNA in each plaque is tested
to see if it will hybridize with the radioactive hemoglobin eDNA nucleic acid com-
plement to the hemoglobin genes being sought. The technique relies on the principle
of complementary base pairing between the cDNA probes and the desired hemo-
globin genes in those very few plaques described in Step 2.
Practical Techniques
After the phages were used to grow E. coli colonies on an agar plate, a piece of filter
paper was placed on the agar and removed. The cells were thus transferred to the
paper, which was placed in a dilute solution of sodium hydroxide (lye or caustic
soda). The first key feature was that the sodium hydroxide caused the hemoglobin
DNA to become single-stranded. The second key feature was that when the single-
stranded,radioactive eDNA was next added, complementary base pairs formed only
if
the filter-paper-bound DNA contained the likewise single-stranded hemoglobin
DNA gene being sought. The radioactive cDNA bound to the filter paper, identifying
the locations of the rabbit hemoglobin gene being sought. The filter paper was next
washed to remove any radioactive probes that were not base paired. X-ray film was
then used to find bacterial colonies containing the hemoglobin gene of interest. This
procedure resulted in a pure culture of
E. coli
in which each cell contained a phage
into which the hemoglobin gene of interest had been cloned.
In summary, the cDNA radioactive probes derived from mRNA were used to

probe the plaques formed from the bacteria-containing phage, which contained
rabbit DNA, and eventually isolate the desired genomic clones of hemoglobin.
9.9 BIOPROCESS ENGINEERING
9.9.1 Bloreactors
A bioreactor is a container or vessel in which a biological reaction occurs. For
example, fermentation takes place in a bioreactor: it is a process of growing (incu-
bating) microorganisms on a substrate containing carbon and nitrogen (the "food"
for the organisms). A natural example of a bioreactor is a pond, which "manufac-
tures" algae or pond scum.
Bioreactors can range from small bench-top fermentors holding 11iter to larger
l-miltion-liter production units. In addition to producing various food products,
bioreactors are used to generate industrial chemicals, enzymes, and biofuels. Using
microorganisms to generate fuel is of particular interest to researchers in energy-
poor countries. In Finland, for example, baker's yeast has been used in a bioelectro-
chemical device in which the chemical process of substrate oxidation-reduction
generates electrical energy.
396
Biotechnology Chap. 9
The biosynthesis process, as well as the resulting relationship between cell
growth and bioproduct formation, differs according to the type of bioreactor. Two
conventional methods are batch and continuous culture fermentation. Bioconver-
sions can also take place on moist but solid substrates.
A primary task in biotechnology processing is to design, operate, and control
bioreactors such that conversion rates and yields are economically feasible. Another
challenge is keeping cells and catalysts alive as they are put through various mashing,
mixing, heating, and other processes. For this reason, bioprocess engineers must not
only be conversant with process development, equipment design,and scale-up but also
understand what is needed to keep organisms viable and growing at an optimal rate.
A common type of bioreactor is a mechanically stirred tank, which utilizes a
three-phase (gas-solid-liquid) reaction. In this type of device, gas is sparged into the

bottom of the vessel, then mixed with the liquid phase of the fermentation process
by a mechanical stirrer (Figure 9.25). There are strict constraints in su.ch a proceS&
For example, a steady supply of oxygen gas bubbles for aerobic fermentations is crit-
ical. Stirring must be rapid enough to disperse gas bubbles, develop a homogenous
liquid, and ensure a solid suspension. Overstirring tends to shear cells, while under-
stirring may asphyxiate them. Another challenge is optimizing heat removal rates;
faster fermentation creates a faster rate of heat production. During scale-up, surface-
to-volume ratios decrease, reducing the rate of heat removal.
Sterility is another major challenge. Processes must be absolutely aseptic. Elim-
ination of unwanted organisms is required to ensure product quality and to prevent
contaminating organisms from displacing the desired production strain. This creates
significant design and operation difficulties, particularly in combination with other
process requirements. For example, a big problem has been designing high-quality
temperature sensors that can stand up to repeated sterilizations.
The molecular reactions inside the bioreactor govern the growth charecteris-
tics of cells. Cell growth patterns depend on a variety of factors, including oxygen
availability, nutrient supply, pH, temperature, and population density. In a typical
batch fermentation, cell growth follows four distinct phases: lag, exponential, sta-
tionary, and decline. Little observable growth occurs in the lag phase, during which
the cell restructures its biosynthetic mechanisms to take account of the environment.
In the exponential phase, the cell grows as quickly as possible given these factors. (In
industrial bioprocessing, this phase is typically measured in terms of the time
required to double the concentration of cells, known as a biomass.) Exponential
growth ceases for a variety of reasons, including nutrient depletion, physical over-
crowding, or buildup of by-products of the metabolic process. There follows a sta-
tionary phase in which the enzymes that catalyzed rapid growth, along with excess
ribosomes, are degraded to create other enzymes or supply fuel for cell maintenance.
When internal energy sources are depleted, the cell is unable to carry out basic func-
tions. The result may be cell lysis (breakage) or inviability (inability to reproduce).
In the depletion phase, the biomass reduces (Figure 9.26).

Optimizing bioreactor functionality involves a number of discrete process
variables, including aeration, agitation, mass and heat transfer, measurement and
control, cell metabolism, and product expression and preparation of inoculates.
Development of expert systems for real-time monitoring and adjustment of the
9.9 Bioprocess Engineering
397
Motor drive
Foam breaker
Cooling coils
Baffle plates
Figure 9.25 A mechanically stirred bioreactor (adapted from Shuler, 1992).
Gearbox
Aseptic seal
Bearing
~ssemblies
Gas exit
Flat blade turbines
Sterile air inlet
Sparger
398
Biotechnology Chap. 9
Time (hours)
Figure 9.26 Batch fermentation growth curve.
fermentation process is one area of research. One key goal is to be able to correctly
identify process problems and correct them online. For a fermentation process, this
includes sensor, equipment, and process failure monitoring. Control and batch
maintenance are also important candidates for automation.
9.9.2 Postprocessing
The bioreactor phase is the heart of the bioprocess. However, the recovery and
purification of a fermentation product are essential to any commercial process. The

degree of difficulty in the recovery and purification process depends heavily on the
nature of the product. Typical downstream product recovery and enrichment pro-
cessing includes filtration, crystallization, and drying techniques. Packaging and ship-
ping the product are also important postprocessing activities.
9.'0 MANAGEMENT OF TECHNOLOGY
9.10.1 Present Trends
Significant advances have been made in a very short time, and these will continue to
foster industrial growth in biotechnology. For example, the Human Genome Project
has been under way since 1990,jointly funded by the National Institutes of Health
and the Department of Energy. Also in May 1998, a collaboration was announced
between The Institute of Genomic Research (TlGR)-a private, nonprofit genetics
laboratory-and Perkin-Elmer-the main manufacturer of DNA sequencing instru-
ments. These projects are focusing on sequencing the 3 billion base pairs of human
DNA and identifying approximately 60,000 to 80,000 human genes. Naturally
enough, these rival projects and enterprises like the Celera Genomics Group, are
creating a highly competitive business environment as they race for completion."
The early phases of such research are devoted to mapping each human chro-
mosome as a step toward ultimately determining all the genes in the DNA sequence.
"ror
popular press reviews, see "The Race 10Cash in on the Genetic Code," The New York
1l'mel;
August29, 1999,Section 3.A1so,Sciou:e News, VoL 154, October 10, 1998,p,239;and The New Yorker, June 12,
2000 p. 66.The Human Genome Project plans to finish sequencing the human genome by 2003 and have
a working draft in 2001.
Stationary growth
pha.,,\
Exponential
phase ,
I
Log

phase
9.10 Management of Technology
399
In the process, researchers are developing methods to automate and optimize
genetic mapping and sequencing.
Subsequent phases will focus on the development of "molecular medicine" based
on early detection of disease, effective preventive medicine, efficient drug develop-
ment, and, possibly, gene therapy or gene replacement. Research efforts are also under
way to sequence the genomes of bacteria, yeast, plants, farm animals, and other organ-
isms. Much of the technology developed during genome research, particularly the
automation and optimization routines, will greatly benefit the biotech industry.
9.10.2
Manufacturing
Despite these advances in knowledge, the path from the laboratory to the market is full
of obstacles. Biotech research is expensive, time-consuming, and frequently fruitless.
The scale-up to economically feasible production levels is also a tremendous challenge.
Biotechnology is in many ways related to one of its parent disciplines, chemical
engineering. However, it is far more difficult because its raw materials, catalysts, and
products are living organisms, which are inherently more fragile and temperamental
than petrochemicals and other substances. Stringent product safety requirements,
especially for therapeutics, create special problems for commercial production.
Equipment and facilities must meet strict safety and quality control standards to
ensure product purity. To date, standards for critical processing components (such as
valve design and function) are still being established, making it difficult to design and
build biotechnology equipment and systems. Lacking manufacturing expertise, many
companies arc sticking to research and licensing their technologies to biotech firms
that have already developed production capabilities. This is similar to the "fabless-
IC" model presented in the management of technology section of Chapter 5.
The long approval process and other product development risks make it espe-
cially important to shorten the critical path for bringing a new product to market.

With the inherent challenges associated with scale-up of industrial bioprocesses, it is
important to begin developing synthesis at the bench and pilot plant scales well
before clinical trials are concluded (Figure 9.27). This is similar to the general push
for concurrent engineering described in several of the earlier chapters.
In addition, there are significant regulatory barriers. New medical compounds
must be rigorously tested in numerous clinical trials using strict Food and Drug
Administration (FDA) regulations. The approval process typically takes from five to
seven years, and the likelihood that a product will fail ishigh. Agricultural regulation
is less rigorous; the federal government recently relaxed its regulations of field
testing and marketing of genetically engineered crops.
9.10.3
Investment
Given the potential range and impact of its commercial applications (Figure 9.28), it
is not surprising that biotech attracts much attention on Wall Street and with venture
capitalists. Throughout the 1980s,hundreds of cash-infused new companies sprouted
up. Each vied to beat the others to market with a breakthrough product. Beginning
in the 19905, the well-known pharmaceutical companies also became involved in
biotech. In many cases, these larger pharmaceuticals bought, or acquired a major
400
Biotechnology Chap. 9
Design
issues
Manufacturing
Issues
F1IUre 9.27 Critical path for biotech design for planning to large-scale
production. (Adapted from O'Connor, 1995
©
1995 IEEE. Reprinted, with
permission, from
iEEE Engineering ill Medicine and Biology,

vot.
14,
no.
2,
p.2rf7,March-ApriI1995.)
interest in, the smaller start-up companies. As a result, today's picture is one in which
a wide range of company types exists. At one extreme, individuals at universities with
molecular and cell biology departments continue to start private research-oriented
companies. The integrity of such practices is discussed in Kenney (1986). At the other
extreme, the large pharmaceuticals have set up production lines for well-established
materials. In between, the industry pioneers such as Chiron and Genentech continue
with a balance of basic research into new products and the production of well-
established products.
9.10.4 The Future
As can be seen in the popular press, biotechnology research creates more ethical
debates than the industries reviewed in Chapters 5 through 8.Part of the controversy
stems from popular fascination and fears about the potential dangers of "messing
with nature." Michael Crichton and Hollywood have helped fuel such concerns with
reconstituted dinosaurs wreaking havoc in tropical islands.
However, beyond the fanciful terrors of science fiction, biotech does indeed
provoke a host of real ethical as well as practical concerns. Selective breeding was
once the only method available to develop desirable plant and animal characteristics
over several generations. By contrast, genetic engineering can clone precisely
defined species. This may be less threatening for the well-known cloning of sheep.
But it is clear from the recent government bans that society feels threatened by the
same possibilities for humans. Does society have the right to intervene so forcefully
in the evolutionary processes? What are the implications for biodiversity?
Privacy and equity are also a concern. Suppose an insurance company decides
to do a DNA test on all its potential clients, and it finds that one of the clients inher-
ited part of some DNA sequence from his or her grandmother that makes the client

a likely candidate for a heart attack at 45.Although the cause is clear, a cure is not
Software
fm
drug design
I
~olecular
biology
Generate
compounds
Molecular
targeting
Bench-scale
synthesis
Pilot-scale
production
Large-scale
manufacturing
9.10 Management of Technology
401
F1gure9.28 The future of biotech.
available yet. As a result, the company refuses to insure the potential client and
informs other insurance companies of the risk factor. Is this ethical'?
9.10.5 Summary
This brief chapter on biotechnology has been included because the field will experi-
ence rapid growth and provide many future career opportunities for people inter-
ested in manufacturing engineering. It can be seen that the issues range from
•••
Biotechnology Chap. 9
interesting scientific principles that are fundamental to life itself, to the engineering
of gene splicing, to the operation of bioreactors, and finally to the ethical issues men-

tioned.
9.11 GLOSSARY
9.11.1 Amino Acids
The building blocks of proteins. There are 20 different amino acids that link together
via peptide bonds during the process of protein synthesis on the surface of the ribo-
some (see Transcription and Translation) according to the genetic information on
mRNA.
9.11.2
Biar.actors
Vessels for biological reaction through fermentation or other transformation
processes. Interferon, for example, is manufactured in a genetically engineered fer-
mentation process.
9.11.3 Biosensors
Combining biology,
Ie-design,
and IC-microfabrication technologies, biosensors are
devices that use a biological element in a sensor. Biosensors work via (a) a biological
molecular recognition element and (b) a physical detector such as optical devices,
quartz crystals, or electrodes.
9.11.4 Cen
The smallest unit of living matter capeblc of self-perpetuation.
9.11.5 Central Dogma
The concept in molecular biology in which genetic information passes unidirec-
tionally from DNA to RNA to protein during the processes of transcription and
translation.
9.11.6 Chromosome
A subcellular structure consisting of discrete DNA molecules, plus the proteins that
organize and compact the DNA.
9.11.7 Codon
A set of three nucleotide bases on the mRNA molecule that code for a specific amino

acid. For example, the codon C·G-Urepresents arginine. There are 64 unique codon
combinations. Some amino acids can be specified by more than one codon sequence.
9.11.8
DNA
(Deoxyribonucleic Acid)
The genetic material in every organism. It is a long, chainlike molecule, usually
formed in two complementary strands in a helical shape.
9.11 Glossary
403
9.11.9 Enzymes
Enzymes are proteins that catalyze reactions.
9.11.10 Fermentation
A process of growing (incubating) microorganisms in a substrate containing carbon
and nitrogen that provide "food" for the organisms.
9.11.11 Gene
The basic unit of heredity, a gene is a sequence of DNA containing the code to con-
struct a protein molecule.
9.11.12 GeneCloning
One of the most common techniques of genetic engineering, gene cloning is a way to
use microorganisms to mass-produce exact replicas of a specific DNA sequence. The
cloned genes are often used to synthesize proteins. The basic technique is to construct
recombinant DNA molecules, insert the resulting DNA sequences into a carrier mole-
cule or vector, and introduce that vector into a host cell so that it propagates and grows.
9.11,13 GeneticCode
Figure 9.14 shows the 64 possible codons and the amino acids specified by each.
9.11.14 Genetic Engineering
The practice of manipulating genetic information encoded in a DNA fragment to con-
duct basic research or to generate a medical or scientific product. Selective breeding
is one of the oldest examples of genetic engineering. The much newer gene cloning
technology is now fairly common practice. Genetic engineering isused in three areas:

to aid basic scientific research into the structure and function of genes, to produce pro-
teins for medical and other applications, and to create transgenic plants or animals.
9.11.15 Genome
The total genetic information of an organism.
9.11.16 Host
A cell used to propagate recombinant DNA molecules.
9,11,17 Natural Selection
The process by which a species becomes better adapted to its environment-the
mechanism behind the evolution of the species. The process depends on genetic
variations produced through sexual reproduction, mutation, or recombinant DNA.
Variant furms that are best adapted tend to survive and reproduce, ensuring that
their genes will be passed on. Over hundreds and thousands of generations, a
species may develop a whole set of features that have enhanced its survival in a
particular environment.
404
Biotechnology Chap. 9
9.11.18 Nucleotide
A building block for DNA and RNA. A nucleotide is composed of three parts: a
sugar, a phosphate, and a chemical base. In DNA, the bases are adenine (A), guanine
(G), thymine (T), and cytosine (C). RNA contains A, G, and C, hut has uracil (U) in
place of thymine.
9.11.19 Proteins
Proteins are long-chained molecules containing chains of amino acids. Twenty dif-
ferent amino acids are used to make proteins.
9.11.20 RNA (Ribonucleic Acid); mRNA; rRNA; tRNA
A long, chainlike molecule formed of the nuc1eotides A, G, U, and C. Cells contain
different RNA types, including messenger RNA (mRNA), ribosomal RNA (rRNA),
and transfer RNA (tRNA). Each type of RNA performs a specific function in pro~
tein synthesis (see Transcription and Translation).
9.1'.21 Recombinant DNA

A DNA molecule made up of sequences originating from two different DNA mole-
cules. Recombination occurs naturally or through genetic engineering, and is a fun-
damental source of genetic diversity. The process usually involves the breaking and
reuniting of DNA strands to produce the new DNA.
9.11.22 Transcription and Translation
The processes by which genetic information on a DNA molecule is used to synthe-
size proteins. During transcription, a strand of mRNA is synthesized from a DNA
template, During translation, the genetic information on mRNA is read by tRNA on
a ribosome (a cell's protein factory) in order to build the chain of amino acids that
form a protein.
9.11.23 Vector
A DNA molecule, usually a phage or plasmid, that is used to introduce DNA into a
host cell for propagation.
9.12 REFERENCES
Avery.0. T., C. M. MacLeod, and M.McCarty.1944.Journal of experimental medicine 78:
137-158.
Campbell,D. 1998.Theapplicationofcombinatorialstrategiesto the identificationofantimi-
crobial agents.Paper presented at the Symposium~n Microarrays and Drug Resistance,the
AmericanSocietyofMicrobiology.Atlanta, GA.
Darnell,
J.,
H. Lodish, and D. Baltimore. 1986.Molecular cell biology. New York:Scientific
AmericanBooks.
9.13 Bibliography
405
Drlica, K. 1992. Understanding DNA and gene cloning: A guide for the curious. New York: John
Wiley
&
Sons.
Economist. 1998. Science and technology. 13 (June): 79-80.

Hershey.A. D., and M. Chase. 1952. Journal of General Physiology 36; 39-56.
Mascarenhas, D. 1999. DNA technology in plain English. Lecture notes from the Symposium
on Twenty-Five Years of Biotechnology, May 13, UC Berkeley Extension.
Nicholl, D. S. T. 1994. An introduction to genetic engineering. Cambridge University.
Okamura, S. M. 1998. Genes required in the a/alpha cell type of saccharomyces cerevisiae,
Ph.D. dissertation. University of California, Berkeley.
Palmiter, R. D., R. L. Brinster, R. E. Hammer, M. E. Trurnbauer, M. G. Rosenfeld, N. C.
Birnberg, and R. M. Evans. 1982. Dramatic growth of mice that develop from eggs microin-
jected with metallothione in Growth hormone fusion genes. Nature 300 (December); 611-615.
Watson,lD.,andEH. C.Crick.1953. Nature 171;737-738,964-967.
watsoaJ.
D., N. H.Hupkins, J. W. Roberts, J. A. Steitz, and A M. Weiner. 1987. Molecular
biology of the gene. Menlo Park, CA: Benjamin Cummings.
9.13 BIBLIOGRAPHY
Bains, W. 1993. Biotechnology: From A to Z. Oxford University.
Baker, A 1994. Engineers further biotechnology's reach. Design News 29: 29.
Berger, S. A, W. Goldsmith, and E. R Lewis. 1996. Introduction to bioengineering. Oxford:
Oxford University Press.
Bruley,D.EI995.An emerging discipline: Focus on biotechnology.1EEE Engineering in Med-
icine and Biology 14 (2): 201.
Bud, R. 1993. The uses of life: A history of biotechnology. Cambridge University Press.
Economist. 1995. A survey of biotechnology and genetics: A special report. 334 (7903)
Ezzell, C 1991. Milking engineered "phann animals." Science News 140 (10): 148.
Kenney, M. 1986. Biotechnology: The university-industrial complex. New Haven; Yale Univer-
sityPress.
O'Connor, G. M.1995. From new drug discovery to bioprocess operations: Focus on biotech-
nology.IEEE Engineering in Medicine and Biology 14 (2): 2m.
Rosenfield, I., E. Ziff, and B.Van Loon. 19B3. DNAfor beginners. Wrilens and Readers, U.S.A
Shuler,M. L.1992. Bioprocess engineering. In Encyclopedia of physical science and technology
2. San Diego, CA; Academic Press.

Timpane,J 1993. Career paths for MS and BS scientists in pharmaceuticals and biotechnology.
Science 261 (5125): 197.
Watson, 1. D. 1968. The double helix. Atheneum Press.
CHAPTER
FUTURE ASPECTS OF
MANUFACTURING
10.1 RESTATEMENT OF GOALS AND CONTEXT
The goals of this book are to:
• Illustrate general principles of manufacturing (Chapters 1and 2).
•Review some of the main manufacturing techniques needed during the
product development cycle
of a consumer electromechanical product (Chap-
ters
3
through 8).
• Review the emerging market of biotechnology manufacturing (Chapter 9).
• Explore management oftechnology and cross-disciplinary issues (Chapter 10).
In a teaching environment,
it
is useful to augment these themes with a
semester-long project in which a simple device is designed, manufactured, and ana-
lyzed from a business viewpoint. It is also beneficial to visit factories and write case
studies on the daily challenges of manufacturing and the future growth of companies.
No one would want to visit a medical doctor who had never had any hands-on expe-
rience. Likewise, students destined for careers in technology can benefit greatly from
seeing the real world of industry early in their careers.
The book is targeted at a class consisting of both engineering and business stu-
dents. This mix of student interests, combined with a focus on group-oriented case
study projects or consulting projects, requires a certain amount of flexibility and
compromise on everyone's part.

The book and its related lectures are deliberately a survey of each manufac-
turing topic and also focus on issues in today's business environment. This has two
obvious limitations:
406
10.2 Management of Technology
407
First, as far as depth is concerned, each of the chapters deals with technical material
that could, on its own, be expanded into a complete textbook. In addition, all the
chapters contain technical material that is somewhat unresolved. Thus the reader is
encouraged to follow the many ASMEIIEEE-type conferences that take place each
year to present the latest research discoveries. Similarly, the management style
reviews, found at the beginning or end of most chapters, could use an expanded, rig-
orous analysis of the type found in the Harvard Business Review or California Man-
agement Review.
Second, there is the problem of keeping the material up to date. Rough drafts of the
book were updated each semester for various manufacturing classes at all levels,
and between each revision substantial changes kept occurring. For example, in
recent years the high-tech community has witnessed the rise of Java and Jini for
embedded systems (see Waldo, 1999); the introduction of network computers such
as the InfoPad; the increased popularity of handheld computers such as the Palm
Pilot; the trend toward the Iz-inch silicon wafer with its $2+ billion plant; and the
continued growth of the U.S. automobile industry. Regretfully, other companies
have experienced a decline. For example, Apple now holds only about 4
%
of the
U.S. market share in personal computers; though, of course, Apple's supporters
hope that its new designs and marketing will change the company's performance for
the better.
10.2 MANAGEMENT OF TECHNOLOGY
Despite the mentioned limitations, especially the changing nature of the world of

technology, there still seems to be the need for a textbook that presents an inte-
grated analysis of the detailed fabrication techniques and the management of
technology.
Management of technology (MOT) can be approximately defined as the set of
activities associated with bringing high-tech products to the marketplace. Specific
issues include:
• Identifying who the customer is
•Analyzing investments in technology; for example, with Hewlett-Packard's
Return Map
• Launching creative products within a "learning organization" that uses TOM
•Fabricating a prototype and scaling up to highly efficient mass production
• Creating new methods of high-technology marketing
•Exploiting Internet-based, business-to-business capabilities; for example, out-
sourcing
This last chapter summarizes the specific methodologies and approaches that
are useful in this integration of the many facets of a high-tech, globally oriented, com-
mercial enterprise.
408
10.3 FROM THE PAST TO THE PRESENT
10.3.1 Mass Production and Taylorism
Future Aspects of Manufacturing Chap. 10
Chapter 1 reviewed the history of manufacturing. It included some details of the
industrial revolution (1780 1820),the importance of interchangeable parts (Colt and
Whitney), and organized mass production with a division between design and man-
ufacturing (Taylor and Ford). In fact, the commercial concept of the division of labor
dates back before the industrial revolution to the beginning of the 18th century,
if
not
earlier. Adam Smith championed it vigorously in his
Inquiry into the Wealth of

Nations (see Plumb, 1965). Frederick Taylor was an even stronger advocate of the
division of labor in his Principles of Scientific Management (1911).
Oriented to the mass production of mass consumption products, Taylorism cre-
ated pyramid-shaped hierarchies with sharply defined boundaries between func-
tional areas such as design, manufacturing, and marketing.
Following the tenets of Taylor's scientific management, creative work was dis-
tinctly segregated from the manual labor performed on the factory floor itself. Shop
floor personnel were called "hired hands" and were actively discouraged from
exerting control over or offering input into the decision-making process. Information
tended to flow down vertical channels in the corporate structure.
In summary, management was strictly top-down, with managers setting every-
thing from high-level corporate objectives to procedural methods at the bottom
rung.
10.3.2 Today's Customized Production
Taylor's structures and practices are poorly suited to the new competitive environ-
ment in which product cycles are short, markets are fragmented, and quality and
speed are of the essence. For example, Curry and Kenney (1999) capture this new
"playing field" in their recent article "Beating the Clock: Corporate Responses to
Rapid Changes in the PC Industry." Section 6.5 of this book reviews these dynamics
in more detail. And of course the popular press frequently picks up the theme. A
recent article in Forbes magazine-"Warehouses That Fly't-c-succinctly captures the
speed of production in the PC industry. In summary, it emphasizes that the "old" idea
that inventory is kept in a big warehouse is dead. For the PC industry in particular,
the inventory is flying through the air in the belly of one of FedEx's or DHL's cargo
planes or being sorted at the airport hub for next-day delivery (Tanzer, 1999).
Overall, what is needed is a cross-functional, interdisciplinary approach that
fosters communication and integration among all parts of an enterprise. A funda-
mental prerequisite is for a firm to become a "learning organization" that constantly
examines its production practices for potential improvements (Cole, 1999). In con-
trast to the compartmentalized mentality of Taylorism, the learning organization

reintegrates manufacturing with planning and creativity. It promotes integrated
problem solving among all groups, including shop floor personnel, production staff,
design engineers, and managers. The chief benefits of this approach are to enhance
learning by doing and develop a cross-disciplinary understanding of product design,
production, and marketing.
10.4 From the Present to the Future
409
10.4 FROM THE PRESENT TO THE FUTURE
10.4.1 The New Competitive Environment
Competing in manufacturing today is very different from even a decade ago, let
alone 100 years ago. For example:
•Fragmented, customized markets have largely replaced mass markets.
•Markets and competition are global.
•Product life cycleshave accelerated significantly.Motorola pagers and cellular
phones have a life cycle of 6 to 12 months. The style of Nike shoes changes
almost once a month depending on the season.
• Customers are more educated and demand many things at once: low prices,
personal service, superior quality and performance, and shorter delivery times.
10.4.2 Generic Technical Solutions
All companies are now aware of the mismatch between rigid Taylorism on the one
hand and demands for rapid response, lean production, and fast-cycle product
development on the other. Helped by newly formed human resource (HR)
departments, such companies strive to develop group problem-solving strategies.
There has also been a trend to use business process reengineering (BPR) and shed
unnecessary layers of middle management. The following innovative process tech-
nologies can then help a company deal with today's competitive pressures in sev-
eral ways:
• Design:
Innovative design methods and DFM/DFA can increase a product's
performance, lower production and material costs, and open new market

opportunities.
• Rapid prototyping:
CAD/CAM and rapid prototyping technologies can accel-
erate time-to-market by improving the design/manufacturing/marketing
interface.
• Computer integrated manufacturing (CIM) systems:
Flexible, reconfigurable
production systems and equipment can help a company operate profitably
even with frequent changes in production volumes and product design.
• Expert systems and databases:
A firm's "knowledge capital" first and foremost
resides with the people in the learning organization. However, their skills and
knowledge can go only so far. Computerized methods for knowledge capture
and dissemination are vital.
• Internet-based, business-to-business collaborations:
Two of the fundamental
technological changes now adding to the World Wide Web's infrastructure
are (a) distributed computing and (b) client-side or browser-side pro-
cessing. These applications are expanding the capabilities of distributed
design, planning, and fabrication environments. Direct business-to-business
transactions, minimizing "markups," are improving the efficiencyof the supply
chain.
.,0
Future Aspects of Manufacturing Chap. 10
10.5 PRINCIPLES OF ORGANIZATIONAL "LAYERING"
The previous section proposed some generic solutions for commercial success. How-
ever, the range of products, processes, and services is so huge that there is rarely a
"one-of-a-kind, miracle technological
solution"
that will give one particular com-

pany a dramatic lead. And even
if
one company does discover a great technology that
puts it ahead for a while, it is usually not long before the competitors catch uP~A
prime example of this might be the original Apple desktop. It has been admired and
copied by everyone else to the point where
it
no longer holds any market edge. Great
technology alone does not win the day, at least not for very long. There is no single
model for success, given the complexity and volatility of markets and technologies.
Thus instead of prescribing a post-muss-production model, it is more useful to
think in terms of general organization and management principles for an intelligent
manufacturing enterprise. The following sections offer general principles that, when
layered upon each other, should be equally applicable to companies dedicated to
mature products needing continuous improvement as well as to companies devel-
oping cutting edge products (see Figure 10.1).
The primary organizational recommendation is to give simultaneous attention
to the following layers:
• I, quality assurance (or TQM) in a learning organization: constantly improve
efficiency in existing operations.
• II, time-to-market: introduce methods and technologies that bring products to
the market first.
• Ill, aesthetics in design: introduce radical product innovations that captivate
consumers. .
Fipre
10.1 A proposed principle of organizational layering as a way to maintain
the growth of the firm: this schematic emphasizes that the greatest business
success arises from being on the early gradients of these new trends.

From bridciM: culture

.From design aesthetics
Note steepest
gradients
-Fromtime-to-market
~
10.6 Layer I: The Learning Organization
411
• IV, cross-disciplinary product development: effectively position the company
for future products that synergistically exploit the overlap between mechan-
ical, electrical, biotechnical, and other disciplines.
Consider Figure 10.1:First.lt may be reasonably proposed thatTQM
1
was first
fuUy exploited by Toyota, Honda, and the Japanese DRAM manufacturers in the
1980s (see Leachman and Hodges, 1996; Cole, 1999; Spear and Bowen, 1999). As
shown on the left side of the figure, they obtained the most benefit from being the
first to champion the TQM movement. After a while, all other manufacturers real-
ized the genuine importance ofTQM. Once this happens, the playing field becomes
level in the figure. A competitive advantage will now no longer come from TQM;
rather, it is a prerequisite for survival.
Second, it may be further proposed that companies such as Intel and Motorola
were the first to exploit time-to-market to the maximum during the early to mid-
1990s.Now all companies are aware of the importance of this concept, and the curve
is flattening out.
Third, it can be reasonably proposed that companies such as Nike, Ford, and
Motorola are some of today's champions of design aesthetics in their market sectors.
These seem to be the first companies that understand that customers and consumers
are now looking beyond TQM and time-to-market to the more subtle expressions of
"flair" or "edge" in product design.
Fourth, it will be argued in Section 10.9 that the next wave of technical prod-

ucts will integrate multiple disciplines, especially exploiting biotechnology. Today's
organizations must be alert to these trends and scenarios-perhaps by creating new
R&D teams or precompetitive "skunk works projects."
10.6 LAVER I, THE LEARNING ORGANIZATION
Cumulative, broad-based learning accelerates subsequent rounds of problem
solving, with the result that overall technical competence and responsiveness
increase with each generation of product. Speaking colloquially, if a company wants
to be a leader in the manufacture of the (n+1)'h generation product, it almost cer-
tainly has to be a leader in the
(n
yh
generation product. This was an essential finding
in Cohen and Zysman's research, reported on in their book Manufacturing Matters
(1987).They argued strongly, with supporting evidence, that the United States should
not give up the manufacturing aspects of product development and merely become
"Ibtai quality management (TQM) is being used here because it is a very familiar term. However,
the actual phraseTQM has fallen out of favor somewhat with practitioners in the quality assurance (QA)
movement, as described by Cole (1999). Cole's colleague Dr. Kano in Tokyo notes that TQM should not
he a series of banners strung up around the factory; indeed the presence of such banners usually means
there is a quality problem! The genuine goals of TQM or QA are to create a corporate culture that
(a) supports and rewards continuous improvement, (b) ensures that continuous innovation illrespected
and accepted as a necessary condition for sustained corporate success, and (c) sets performance standards
and pay raises based on quality achievement.
4'2
Future Aspects of Manufacturing Chap. 10
a service industry to the world.' Even though companies might subcontract special-
ized manufacturing functions (such as rapid prototyping by SLA),
it
is still crucial to
be working as an integrated team with the subsuppliers.

Such integrated teams consisting of the original product designers and selected
subsuppliers should have the following characteristics:
• Cross-functional teams must bear shared responsibilities.
• All team members must be held accountable for the team's performance.
• Managers must empower individuals and facilitate teams.
• All functional units must cooperate to achieve a common goal.
• Conflicts should be resolved at the level where the best information and
knowledge exist to address the problem.
Observers emphasize that the Dpenness of an intranet brings out even more
need for honest sharing of ideas inside a learning organization. But how far and to
what level of sharing a firm must go outside its boundaries to all suppliers is still
something that business-to-business relationships are struggling to understand. This
section includes a recent quote from the Economist (Symonds, 1999):
In the past the rules of businesswere simple:beat the competition into submis-
sion, squeeze your suppliers, and keep your customers ignorant the better to
gouge them.At least everybody knew where they stood. The new technology
makes an unprecedented degree of collaboration possible,but nobody can pre-
dict how far that willreach outside the boundaries of individualfirms.
Berners-Lee (1997) and Shapiro and Varian (1999) describe this broader col-
laboration as establishing a collective information universe for an enterprise or
alliance. It is analogous to a legal system where individuals act according to their own
drives but in the context of a macroscopic understanding of the bigger picture and
its morals. Extrapolated to the firm, or an alliance of firms, the intention would be to
establish an information universe where all members would instinctively resonate
with global performance criteria.
The university environment that might create the "lifelong learning" opportu-
nities Ior members of such a learning organization is described in a forward-looking
article by Lee and Messerschmitt (1999). One key idea is to return to the "Oxbridge''
model of small, village-like learning communities led by a resident tutor. These might
exist inside a company but have broader ties to a nearby major university, where spe-

cial events occur and from which professors can link to these distributed "learning
villages."
lDuring the 1992 presidential campaign, one of then-President George Bush's advisers announced
that "it doesn't matter
if
the United States is making computer chips or potato chips." Luckily, this atn-
tude does not seem to have prevailed into the next century.
10.7 Layer II: Compressing Time-to-Market 413
10.7 LAYER II: COMPRESSING TIME·TO·MARKET
For many years,companies focused on product design and treated manufacturing as
a constant factor or as a separate
ex post
concern. This has now changed. In all indus-
tries, the simultaneous design of
product and process
has been shown to be a "best
practice" (Black, 1991;Leachman and Hodges, 1996).
Outsourcing of manufacturing to specialists increases, rather than decreases,
the need for simultaneous design of product and process. As recommended in
Koenig (1997), Borrus and Zysman (1997), Handfield and associates (1999), and
Cole (1999), all subsuppliers and final customers must be brought into the concur-
rent design and continuous improvement loop. Employees are encouraged to
interact with their peers outside of the firm. The goals are to stay on top of manu-
facturing developments in their field and to pursue distance learning/continuing edu-
cation opportunities in manufacturing processes that have been outsourced. Even
though the physical manufacturing process may be outsourced, the internal
designers must still keep pace with the knowledge in that field.
In summary,for all firms,the manufacturing process is always a part of a larger
production chain extending from subsuppllers through the firm to its customers.
When technologies and products change rapidly, arm's-length relationships among

companies can make it difficult to respond quickly.A firm's suppliers and customers
are an important source of ideas and problem-solving capabilities. If, for example, a
particular design modification changes the specifications for one or more compo-
nents, it isuseful to coordinate the proposed change with that component's supplier
in order to bring in the supplier's ideas and alert it to changes it may need to make
to its own processes.Vice versa, the potential of new manufacturing methods must
be put in the hands of component designers so that they can exploit new procedures
and ideas.
The following infrastructural tools have been shown to significantly compress
time-to-market and to foster bidirectional communications between design and
manufacturing:
• Concurrent engineering (Chapter 3)
•Rapid prototyping (Chapter 4)
• Computer integrated manufacturing (Chapters 5 through 8)
•Expert systems and database management (Chapter 8)
• Internet-based collaborations (Chapter 4)
As a firstexample,this explainsthe sustained successofcompanies such as Intel,
in whicheach successivegeneration of ICs gets produced faster than the one before.
As a second example, the design and manufacture of the InfoPad, described in
Chapter 6, were accelerated by the use of DUCADE (Wang et al., 1~96).This soft-
ware environment for electromechanical products performed electrical CAD and
mechanical CAD concurrently.